Triptans are pharmaceutical active ingredients that are used for the treatment of migraine attacks, in particular acute Cluster Headache that represents a true therapeutic emergency.
Sumatriptan is the major anti-migraine pharmaceutical agent and the reference pharmaceutical agent on the market, but all triptans have the same physico-chemical nature and the same mode of central vascular action. In particular, Zolmitriptan, Almotriptan, Eletriptan, Naratriptan and Frovatriptan are known.
The triptans have the capacity to stimulate certain receptors of serotonin and more specifically the vascular receptors with 5-hydroxytryptamine 1 (5-HT1). The stimulation of these receptors causes central vasoconstriction reducing the vasodilatation phenomena and edema at the origin of the VAF attack.
It is known that triptans can be administered intravenously by drip, but this route has remained experimental because of the difficulty of its current therapeutic application, although such an administration has demonstrated a very short delay in effective clinical response for a very low dose that is administered.
Actually, this method of administration, requiring dedicated personnel and the use of specific equipment, has a high cost, is cumbersome for the patient who is subjected to hospitalization, and is not suitable for the treatment of migraine attacks. Consequently, although the benefits of the intravenous administration of triptans have been clinically evaluated and are extremely satisfactory, commercial use of these intravenous, specific galenical forms has never been undertaken.
With the attacks being unpredictable, certain patients need daily treatment, so that only self-administration is possible.
There are currently several methods for self-administration of triptans.
A first known method is the administration in the form of tablets.
Nevertheless, the triptans that are administered enterally do not work for about two hours, an excessive delay for any suffering patient who is waiting.
When they are introduced into the alimentary canal and the stomach, these active ingredients undergo the so-called “first digestive pass” effect, alterations and losses linked to the stomach environment or to variations of intestinal physiologies, including gastric stasis, paralysis thoroughly described as constant in the individuals suffering from migraines, which reduces the absorption of any active ingredient by at least 50%.
They are then subjected to a so-called “first hepatic pass” effect, which causes their more or less intense metabolization and/or their degradation, with the composition of numerous metabolites, for the most part inactive or toxic, causing secondary effects.
The dose of truly bioavailable active ingredient is therefore extremely small: only one very residual part of the quantity that is administered remains valid for producing the expected pharmacological effect.
Thus, by way of example, administered via the digestive tract, Sumatriptan has a residual bioavailability that is reduced to less than 14% of the administered dose, simultaneously with a mean volume of theoretical distribution in the human body of 200 liters and a half-life of 2 hours only when the maximum plasmatic concentration is reached only after 1 to 1.5 hours.
It is also known that the onset of a clinical effect on the ailment on average begins only 30 minutes after intake.
Actually, there are two major problems.
The first problem is that it is necessary to administer a sufficient dose of triptan to the patient, taking into account the weight status of the subject, the absorption, the metabolization, the dilution and the dispersion of this active ingredient in the organism, so that the sole active residual part reaches the vascular receptors with 5-hydroxytryptamine 1 (5-HT1) and produces pharmacological effectiveness.
The second is the fixed latency period linked to absorption, to metabolization, and to the diffusion of the active ingredient in the organism before the molecule acts and of which the patient perceives the beneficial effects.
The administration of triptans using tablets via the digestive tract is therefore suitable neither in rapidly effective treatment of migraines nor in the emergency of a cataclysmic headache such as acute Cluster Headache.
Other possible means for self-administration of triptans, such as the buccal permucous means, the nasal permucous means, and the subcutaneous injectable means, are also known.
The buccal permucous means makes it possible to administer medications by passive passage of sublingual, jugal, gingival, lingual, palatal, or pharyngeal mucous membranes, and then passage into the sublingual veins and cardiac distribution, and with general circulation, thus short-circuiting the digestive passage and the hepatic metabolism.
Nevertheless, the existing formulations, such as the orodispersible Zolmitriptan tablets, are not satisfactory, in particular because of the fact that the triptans are by nature insoluble in biological liquids such as saliva. For these forms, if their dispersibility is oral, the insoluble active ingredient is then swallowed and undergoes the same kind of digestive metabolism as that of the triptan forms in tablets, which shows the equivalence of bioavailability claimed by these two forms—orodispersible and tablet—in their legal notes.
This is also the case of sprays and chewable gelatin capsules that are designed for a transmucous administration, described in the application WO-2005/032518. These formulations have characteristics that are not satisfactory in terms of precision of administration, absorption yields and ensured bioavailability of administered dosages.
It is a matter of complex liquid formulations that comprise a combination of multiple ingredients designed to solubilize and stabilize Sumatriptan molecules, in particular propylene glycol, polyethylene glycol, benzoic acid, etc., and to create a very specific state of viscosity for a spray distribution. During administration, the distribution in the buccal cavity nevertheless remains diffuse and random, and upon reception of the spray-propelled particles, the latter are instantaneously mixed with the saliva that is produced in a reflexive and mechanical manner in the buccal cavity. This mixture is generally swallowed automatically by the patient before the active ingredient has had the opportunity to pass through the buccal mucous membranes to pass into the venous vascular stream. Only a very small fraction of the formulated active ingredient is therefore directly available by permucous passage, around 20 to 25% of the administered unit dose, and the effectiveness also remains very far from that obtained by intravenous or subcutaneous means.
The nasal method makes possible a permucous absorption of the active ingredient by spraying a liquid form (spray). In the field of anti-migraine agents, in particular nasal sprays that consist of basic Sumatriptan in aqueous solution with 4 vehicles are known (Imigrane). If this nasal means has shown a dose/effect yield that is slightly better than the enteric means, the maximum concentration of Sumatriptan is evaluated between 13.1 and 14.14 ng/ml of plasma 30 minutes after the administration of a single intra-nasal dose of 20 mg. The mean bioavailability of the administered dose is therefore not greater than 10%. This inadequate yield is also always random because of the possible occupancy of nasal passages by mucus. Thus, these formulations for administration via the nasal passages are no longer satisfactory.
There is also another method of administration that was developed twenty years ago for Sumatriptan: the subcutaneous injectable pathway, when administered by doctor or nurse or by self-injection. Studies have shown that the subcutaneous injection of Sumatriptan with a single dosage of 6 mg produces 75% of remission of the acute Cluster Headache attack in a mean delay of 15 minutes.
However, this method of administration, which represents a high unit cost, requires the use of a specific piece of equipment, a self-injecting device; even for a patient in a true attack, it proves to be not very ergonomic, and it is painful and much more invasive than the simple intake of tablets or the use of a spray.
In addition, although the exclusive form of self-administration is the most effective that currently exists for treatment of the attack, it still remains very far from the effectiveness obtained by intravenous means that produces 90% of remissions after 3 to 4 minutes.